Idiopathic CD4⁺ lymphocytopenia (ICL) is defined by a stable loss of CD4⁺ T cells in the absence of any known cause of immune deficiency. This syndrome is still of undetermined origin. It affects adult patients, some of them displaying opportunistic infections similar to HIV-infected subjects. The hypothesis that the cellular immune defect may be due to biochemical failures of the CD3–TCR pathway is investigated here in a patient associating a severe selective CD4⁺ lymphocytopenia with an increased CD8⁺ T cell count discovered in the course of a cryptococcal meningitidis. A 40% reduction of T cell proliferation to CD3–TCR stimulation is observed only in the CD4⁺ subpopulation. The early CD3-induced protein tyrosine phosphorylations are conserved in both CD4⁺ and CD8⁺ subsets, and the levels of the T cell protein tyrosine kinases p56^Lck, p59^Fyn and ZAP-70 are normal. However, we find a 50% reduction of p56^Lck kinase activity in the patient's T cells compared to a healthy control donor. p59^Fyn activity does not appear to be altered. Nevertheless, we do not find any genetic abnormality of p56^Lck. These results thus suggest that a defect of an unknown protein regulating p56^Lck activity takes place in this patient's T cells. Taken together, these findings reveal p56^Lck alteration in ICL and confirm the critical role of this kinase in the maintenance of the peripheral CD4⁺ T cell subpopulation.